Heterocyclic retinoid compounds

ABSTRACT

The current invention provide novel heterocyclic retinoid compounds, methods of treating or preventing chronic obstructive pulmonary disease, cancer and dermatological disorders, pharmaceutical compositions suitable for the treatment or prevention of these disorders and methods for delivering formulations of these retinoids to a mammal having these disorders.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. 119(e) ofU.S. Provisional Application Serial No. 60/335,129, filed Oct. 31, 2001,hereby incorporated by reference in its entirety.

1. FIELD OF THE INVENTION

[0002] The invention relates to novel heterocyclic retinoid compoundsand methods of synthesis thereof. The invention also relates to methodsof using these heterocyclic retinoid compounds and pharmaceuticalcompositions thereof.

2. BACKGROUND OF THE INVENTION 2.1. Retinoids

[0003] The retinoids are structural analogues of vitamin A and includeboth natural and synthetic compounds. Retinoid compounds such as alltrans retinoic acid (“ATRA”), 9-cis-retinoic acid, trans 3-4didehydroretinoic acid, 4-oxo retinoic acid, 13-cis-retinoic acid andretinol are pleiotrophic regulatory compounds that influence a largenumber of inflammatory, immune and structural cells.

[0004] For example, retinoids modulate epithelial cell proliferation,morphogenesis in lung and differentiation through a series of hormonenuclear receptors that belong to the steroid/thyroid receptorsuperfamily. The retinoid receptors are classified into the retinoicacid receptors (RAR) and the retinoid X receptors (RXR) each of whichconsists of three distinct subtypes (α, β and γ).

[0005] ATRA is the natural ligand for the retinoic acid receptors andbinds with similar affinity to the α, β and γ subtypes. A quantitativestructure-activity relationship has been established for a number ofsynthetic RAR α, β and γ retinoid agonists, which has elucidated theprincipal electronic and structural characteristics that provideselective affinity for each RAR subtype (Douget et al., Quant. Struct.Act. Relat., 18, 107, 1999).

[0006] ATRA does not bind to RXR, for which 9-cis-retinoic acid is thenatural ligand. A number of synthetic RXR and RAR α, β and γ retinoidagonists have also been described in the art (See, e.g., Billoni et al.,U.S. Pat. No. 5,962,508; Belloni et al., WO 01/30326, published May 3,2001; Klaus et al., U.S. Pat. No. 5,986,131; and Bernardon et al.,WO92/06948, published Apr. 30, 1992). Other retinoid patents includeBernadon, U.S. Pat. Nos. 5,716,624 and 6,046,220.

2.2. Therapeutic Uses of Retinoids in Dermatology and Cancer

[0007] In tissues other than pulmonary tissues, retinoids typically haveanti-inflammatory effects, can alter the progression of epithelial celldifferentiation and may inhibit stromal cell matrix production. Thesebiological effects of retinoids have led to the development of manytopical agents for dermatological disorders such as psoriasis, acne andhypertrophic cutaneous scars. Retinoids have also been used in thetreatment of light and age damaged skin, the healing of wounds caused,for example, by surgery and burns (Mustoe et al., Science 237, 13331987; Sprugel et al., J. Pathol., 129, 601, 1987; Boyd, Am. J. Med., 86,568, 1989) and as anti-inflammatory agents for treatment of arthritis.Other medicinal applications of retinoids include the control of acutepromyelocytic leukemia, adeno and squamous cell carcinoma and hepaticfibrosis. Retinoids have also been used extensively in treatment ofpremalignant epithelial lesions and malignant tumors (carcinomas) ofepithelial origin (Bollag et al., U.S. Pat. No. 5,248,071; Spom et al.,Fed. Proc. 1976, 1332; Hong et al., “Retinoids and Human Cancer” in TheRetinoids: Biology, Chemistry and Medicine, M. B. Sporn, A. B. Robertsand D. S. Goodman (eds.) Raven Press, New York, 1994, 597-630). However,many known retinoids lack selectivity and consequently exert harmfulpleiotrophic effects that may cause patient death when used intherapeutically effective amounts. Thus, the therapeutic use ofretinoids in diseases other then cancer has been limited by toxic sideeffects. A general review of retinoids can be found in Goodman &Gilman's “The Pharmacological Basis of Therapeutics”, Chapters 63-64,9^(th) edition, 1996, McGraw-Hill.

2.3. Emphysema

[0008] Chronic Obstructive Pulmonary Disease (“COPD”) refers to a largegroup of lung diseases which prevent normal respiration. Approximately11% of the population of the United States has COPD and available datasuggests that the incidence of COPD is increasing. Currently, COPD isthe fourth leading cause of mortality in the United States.

[0009] COPD is a disease in which the lungs are obstructed due to thepresence of at least one disease selected from asthma, emphysema andchronic bronchitis. The term COPD was introduced because theseconditions often co-exist and in individual cases it may be difficult toascertain which disease is responsible for causing the lung obstruction(1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratoryflow from the lungs that is constant over several months and in the caseof chronic bronchitis persists for two or more consecutive years. Themost severe manifestations of COPD typically include symptomscharacteristic of emphysema.

[0010] Emphysema is a disease where the gas-exchange structures (e.g.,alveoli) of the lung are destroyed, which causes inadequate oxygenationthat may lead to disability and death. Anatomically, emphysema isdefined by permanent airspace enlargement distal to terminal bronchioles(e.g., breathing tubes) which is characterized by reduced lungelasticity, decreased alveolar surface area and gas exchange andalveolar destruction that results in decreased respiration. Thus, thecharacteristic physiological abnormalities of emphysema are reduced gasexchange and expiratory gas flow.

[0011] Cigarette smoking is the most common cause of emphysema althoughother environmental toxins may also contribute to alveoli destruction.The injurious compounds present in these harmful agents can activatedestructive processes that include, for example, the release ofexcessive amounts of proteases that overwhelm normal protectivemechanisms, such as protease inhibitors present in the lung. Theimbalance between proteases and protease inhibitors present in the lungmay lead to elastin matrix destruction, elastic recoil loss, tissuedamage, and continuous lung function decline. The rate of lung damagemay be decreased by reducing the amounts of toxins in the lung (i.e., byquitting smoking). However, the damaged alveolar structures are notrepaired and lung function is not regained. At least four differenttypes of emphysema have been described according to their locations inthe secondary lobule: panlobar emphysema, centrilobular emphysema,distal lobular emphysema and paracicatrical emphysema.

[0012] The major symptom of emphysema is chronic shortness of breath.Other important symptoms of emphysema include, but are not limited to,chronic cough, coloration of the skin caused by lack of oxygen,shortness of breath with minimal physical activity and wheezing.Additional symptoms that may be associated with emphysema include butare not limited to vision abnormalities, dizziness, temporary cessationof respiration, anxiety, swelling, fatigue, insomnia and memory loss.Emphysema is typically diagnosed by a physical examination that showsdecreased and abnormal breathing sounds, wheezing and prolongedexhalation. Pulmonary function tests, reduced oxygen levels in the bloodand a chest X-ray may be used to confirm a diagnosis of emphysema.

[0013] No effective methods for reversing the clinical indications ofemphysema currently exist in the art. In some instances, medicationssuch as bronchodilators, β-agonists, theophylline, anticholinergics,diuretics and corticosteroids delivered to the lung by an inhaler ornebulizer may improve respiration impaired by emphysema. Oxygentreatment is frequently used in situations where lung function has beenso severely impaired that sufficient oxygen cannot be absorbed from theair. Lung reduction surgery may be used to treat patients with severeemphysema. Here, damaged portions of the lung are removed, which allowsthe normal portions of the lung to expand more fully and benefit fromincreased aeration. Finally, lung transplantation is another surgicalalternative available to individuals with emphysema, which may increasequality of life but does not significantly improve life expectancy.

2.4. Lung Development, Alveolar Septation and Use of Retinoids inTreating Emphysema

[0014] Alveoli are formed during development by division of sacculesthat constitute the gas-exchange elements of the immature lung. Theprecise mechanisms governing formation of septa and their spacing remaincurrently unknown in primates. Retinoids such as ATRA, which is amultifunctional modulator of cellular behavior that may alter bothextracellular matrix metabolism and normal epithelial differentiation,have a critical regulatory role in mammals such as the rat. For example,ATRA modulates critical aspects of lung differentiation through bindingto specific retinoic acid receptors that are selectively temporally andspatially expressed. Coordinated activation of different retinoic acidreceptors subtypes has been associated with lung branching,alveolization/septation and gene activation of tropoelastin in neonatalrats.

[0015] During alveolar septation, retinoic acid storage granulesincrease in the fibroblastic mesenchyme surrounding alveolar walls (Liuet al., Am. J. Physiol. 1993, 265, L430; McGowan et al., Am. J.Physiol., 1995, 269, L463) and retinoic acid receptor expression in thelung peaks (Ong et al., Proc. Natl. Acad. of Sci., 1976, 73, 3976;Grummer et al., Pediatr. Pulm. 1994, 17, 234). The deposition of newelastin matrix and septation parallels depletion of these retinoic acidstorage granules. Postnatal administration of retinoic acid has beenshown to increase the number of alveoli in rats, which supports theconcept that ATRA and other retinoids may induces alveoli formation(Massaro et al., Am. J. Physiol., 270, L305, 1996). Treatment of newbornrat pups with dexamethasone, a glucocorticosteroid, prevents septationand decreases expression of some sub-types of retinoic acid receptor.Supplemental amounts of ATRA have been shown to prevent dexamethasoneinhibition of alveoli formation. Further, ATRA prevents dexamethasonefrom diminishing retinoic acid receptor expression and subsequentalveolar septation in developing rat lung.

[0016] ATRA has been reported to induce formation of new alveoli andreturns elastic recoil in the lung to approximately normal values inanimal models of emphysema (Massaro et al., Nature Med., 1997, 3, 675;“Strategies to Augment Alveolization,” National Heart, Lung, and BloodInstitute, RFA: HL-98-011, 1998; Massaro et al., U.S. Pat. No.5,998,486). However, the mechanism of action of ATRA in these studiesremains undefined, although Massaro reports that ATRA generates newalveoli. More importantly, the use of ATRA presents several toxicity oradverse effects concerns.

[0017] Thus, novel retinoid agonists useful for treating dermatologicaldisorders, disorders of the lung such as COPD, emphysema and cancerwithout the toxicity problems of ATRA or other retinoids are highlydesirable.

3. SUMMARY OF THE INVENTION

[0018] The current invention provides novel heterocyclic retinoidcompounds, methods of treating or preventing disorders of the lung suchas chronic obstructive airway disorders, cancer and dermatologicaldisorders, pharmaceutical compositions suitable for the treatment orprevention of such diseases or disorders and methods for deliveringformulations of novel heterocyclic retinoid compounds into the lung of amammal suffering from such diseases or disorders. In one embodiment, thepresent invention provides compounds according to structural formula(I):

[0019] or a pharmaceutically acceptable salt, solvate or hydrate thereofwherein:

[0020] n is an integer from 0 to 2;

[0021] A is aryl or heteroaryl;

[0022] Bis O, S or NR^(6;)

[0023] R⁶ is hydrogen or alkyl;

[0024] Y is —OR⁷, —SR⁷ or —NR⁸R⁹;

[0025] R⁷ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl orcycloalkyl-alkyl;

[0026] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, arylalkyl,cycloalkyl or cycloalkyl-alkyl or together with the nitrogen atom towhich they are attached form a heterocycloamino ring;

[0027] Z is —C(R¹⁰¹)₂—, —R¹⁰²C═CR¹⁰²—, —C≡C—, —C(R¹⁰³)₂S—, —C(O)O— or—C(O)NR¹⁰—;

[0028] each of R¹⁰, R¹⁰¹, R¹⁰² and R¹⁰³ is independently hydrogen oralkyl;

[0029] R¹ and R² are independently hydrogen or alkyl;

[0030] R³ is hydrogen, alkyl; and

[0031] R⁴ and R⁵ are independently hydrogen, (C₁-C₈) alkyl or arylalkyl.

[0032] The present invention encompasses the use of the compounds of theinvention to treat or prevent certain chronic obstructive airwaydisorders, particularly chronic obstructive pulmonary disease includingchronic bronchitis, emphysema and asthma in mammals, especially humansthat smoke or smoked cigarettes. In a preferred embodiment, theinvention encompasses the treatment or prevention of panlobar emphysema,centrilobular emphysema or distal lobular emphysema in mammals usingnon-toxic and therapeutically effective doses of the compounds of theinvention.

[0033] The present invention also encompasses the use of the compoundsof the invention for treating or preventing cancer or dermatologicaldisorders. Further, the instant invention encompasses the use ofpharmaceutical compositions of the compounds of the invention to treator prevent chronic obstructive airway disorders, cancer ordermatological disorders. Moreover, the invention encompasses the use ofelectrohydrodynamic aerosol devices, aerosol devices and nebulizers todeliver formulations of compounds of the invention into the lung of amammal suffering from or at risk of chronic obstructive airway disordersor cancer.

[0034] The invention also encompasses the systemic use as well as thelocal use of the compounds of the invention or both in combination.Either or both can be achieved by the oral, mucosal or parenteral modesof administration. As mentioned above, means of delivering compounds ofthe invention directly into the lung by nebulizer, inhaler or otherknown delivery devices are encompassed by the invention. A method fortreatingchronic obstructive airway disorders, cancer or dermatologicaldisorders by combining compounds of the invention with one or moreadditional therapies is also encompassed by the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

[0035] As used herein the term “compounds of the invention” means thecompounds of generic formula (I) including but not limited to specificcompounds within those formulas disclosed herein. The compounds of theinvention are identified herein by their chemical structure and/orchemical name. Where a compound is referred to by both a chemicalstructure and a chemical name and the chemical structure and chemicalname conflict, the chemical structure is determinative of the compound'sidentity. The compounds of the invention may contain one or more chiralcenters and/or double bonds and therefore, may exist as stereoisomers,such as double-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to the invention, the chemical structuresdepicted herein, and therefore the compounds of the invention, encompassall of the corresponding compound's enantiomers and stereoisomers, thatis, the stereoisomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can beresolved into their component enantiomers using either separationtechniques or chiral synthesis techniques known in the art.

[0036] “Acyl” means a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl or arylalkyl wherein alkyl,cycloalkyl, cycloalkyl-alkyl, aryl and arylalkyl are as defined herein.Representative examples include, but are not limited to formyl, acetyl,cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl,and the like.

[0037] “Acylamino” means a radical —NR′C(O)R, where R′ is hydrogen oralkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl orarylalkyl wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl andarylalkyl are as defined herein. Representative examples include, butare not limited to formylamino, acetylamino, cylcohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, andthe like.

[0038] “Alkoxy” means a radical —OR where R represents an alkyl group asdefined herein e.g., methoxy, ethoxy, propoxy, butoxy and the like.

[0039] “Alkoxycarbonyl” means a radical —C(O)-alkoxy where alkoxy is asdefined herein.

[0040] “Alkyl” means a linear saturated monovalent hydrocarbon radicalof one to eight carbon atoms or a branched saturated monovalenthydrocarbon radical of three to eight carbon atoms, e.g., methyl, ethyl,propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.

[0041] “Alkylamino” means a radical —NHR where R represents an alkyl,cycloalkyl or cycloalkyl-alkyl group as defined herein. Representativeexamples include, but are not limited to methylamino, ethylamino,isopropylamino, cyclohexylamino, and the like.

[0042] “Alkylene” means a linear saturated divalent hydrocarbon radicalof one to ten carbon atoms or a branched saturated divalent hydrocarbonradical of three to ten carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

[0043] “Alkylsulfonyl” means a radical —S(O)₂R where R is an alkyl,cycloalkyl or cycloalkyl-alkyl group as defined herein, e.g.,methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and thelike.

[0044] “Alkylsulfinyl” means a radical —S(O)R where R is an alkyl,cycloalkyl or cycloalkyl-alkyl group as defined herein e.g.,methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and thelike.

[0045] “Alkylthio” means a radical —SR where R is an alkyl, cycloalkylor cycloalkyl-alkyl group as defined herein e.g., methylthio, ethylthio,propylthio, butylthio, and the like.

[0046] “Aryl” means a monocyclic or bicyclic aromatic hydrocarbonradical which is optionally substituted with one or more substituents,preferably one, two or three, substituents preferably selected from thegroup consisting of acyl, alkyl, acylamino, alkoxycarbonyl, alkyamino,alkylsulfinyl, alkylsulfonyl, alkylthio, alkoxy, amino, carbamoyl,cyano, dialkylamino, ethylenedioxy, halo, haloalkyl, heteroalkyl,hydroxy, hydroxyalkyl, methylenedioxy, nitro and thio. More specificallythe term aryl includes, but is not limited to, phenyl, chlorophenyl,fluorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl and the derivativesthereof.

[0047] “Arylalkyl” refers to an alkyl radical as defined herein in whichone of the hydrogen atoms of the alkyl group is replaced with an arylgroup. Typical arylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like.

[0048] “Aryloxy” means an —O-aryl group where aryl is as defined herein.

[0049] “Arylalkyloxy” means an —O-arylalkyl group where arylalkyl is asdefined herein.

[0050] “Carbamoyl” means the radical —C(O)N(R)₂ where each R group isindependently hydrogen or alkyl as defined herein.

[0051] “Carboxy” means the radical —C(O)OH.

[0052] “Cyano” means the radical —CN.

[0053] “Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbonradical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl,cyclohexyl, 4-methylcyclohexyl and the like.

[0054] “Cycloalkyl-alkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a cycloalkyl group as defined herein, e.g.,cyclohexylmethyl and the like.

[0055] “Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, cycloalkyl or cycloalkyl-alkyl group as definedherein. Representative examples include, but are not limited todimethylamino, methylethylamino, di-(1-methylethyl)amino,(cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino,(cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino,(cyclohexylmethyl)(ethyl)amino and the like.

[0056] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoroand chloro.

[0057] “Haloalkyl” means an alkyl group substituted with one or moresame or different halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃ andthe like.

[0058] “Heteroalkyl” means an alkyl radical as defined herein whereinone or more hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkyl-alkyl; R^(b) and R^(c) areindependently of each other hydrogen, acyl, alkyl, cycloalkyl, orcycloalkyl-alkyl; and when n is 0, R^(d) is hydrogen, alkyl, cycloalkyl,or cycloalkyl-alkyl, and when n is 1 or 2, R^(d) is alkyl, cycloalkyl,cycloalkyl-alkyl, amino, acylamino, alkylamino, or dialkylamino.Representative examples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[0059] “Heteroaryl” means means a monocyclic or bicyclic radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring isoptionally substituted independently with one or more substituents,preferably one or two substituents, selected from alkyl, haloalkyl,heteroalkyl, halo, hydroxy, alkoxy, nitro, cyano, cycloalkyl,cycloalkylalkyl, —COR (where R is alkyl or optionally substitutedphenyl, —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R is hydrogen, alkyl,cycloalkyl or cycloalkylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where nis an integer from 0 to 5, R′ and R″ are independently hydrogen oralkyl, and R^(a) and R^(b) are, independently of each other, hydrogen,alkyl, cycloalkyl or cycloalkylalkyl, or R^(a) and R^(b) together withthe nitrogen atom to which they are attached form a heterocyclyl ring).More specifically the term heteroaryl includes, but is not limited to,pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl,imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl,tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl,benzisoxazolyl or benzothienyl, and the derivatives thereof.

[0060] “Heterocycloamino” means a saturated monovalent cyclic group of 4to 8 ring atoms, wherein at least one ring atom is N and optionallycontains one additional ring heteroatom selected from the groupconsisting of N, O, or S(O)_(n) (where n is an integer from 0 to 2), theremaining ring atoms being C. The heterocyclyl ring may be optionallysubstituted independently with one, two, or three substituents selectedfrom alkyl, haloalkyl, heteroalkyl, acyl, halo, nitro, carboxy, cyano,cyanoalkyl, hydroxy, alkoxy, amino, alkylamino or dialkylamino. Morespecifically the term heterocyclyl includes, but is not limited to,piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide,thiomorpholino-1,1-dioxide, and the derivatives thereof.

[0061] “Hydroxyalkyl” means an alkyl radical as defined herein,substituted with one or more hydroxy groups, provided that the samecarbon atom does not carry more than one hydroxy group. Representativeexamples include, but are not limited to, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl,2-hydroxybutyl,

[0062] 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,2-hydroxy-1-hydroxymethylethyl,

[0063] 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly,as used herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

[0064] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy(e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

[0065] “Pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

[0066] “Pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

[0067] The terms “pro-drug” and “prodrug” are used interchangeablyherein and refer to any compound which releases an active parent drugaccording to structural formula (I) in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of a compound ofstructural formula (I) are prepared by modifying one or more functionalgroup(s) present in the compound of structural formula (I) in such a waythat the modification(s) may be cleaved in vivo to release the parentcompound. Prodrugs include compounds of structural formula (I) wherein ahydroxy, amino, or sulfhydryl group in a compound of structural formula(I) is bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, esters (e.g., acetate,formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of structuralformula (I) and the like.

[0068] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in T. W.Green and P. G. Futs, “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC)and the like. Representative hydroxy protecting groups include but arenot limited to, those where the hydroxy group is either acylated oralkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

[0069] As used herein, the term “mammal” includes human. The terms“human” and “patient” are used interchangeably herein.

[0070] “Treating” or “treatment” of chronic obstructive pulmonarydisorder, emphysema, cancer or a dermatological disorder includespreventing the disease, (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a mammal that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease) inhibiting the disease (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms) or relieving the disease, (i.e., causing regression of thedisease or at least one of the clinical symptoms). Preventing orprevention encompasses administration prior to manifestation of thedisease or disorder.

[0071] “A therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

[0072] Reference will now be made in detail to preferred embodiments ofthe invention. While the invention will be described in conjunction withpreferred embodiments, it should be understood that it is not intendedto limit the invention to these preferred embodiments. To the contrary,it is intended to cover alternatives, modifications, and equivalents asmay be included within the spirit and scope of the invention as definedby the appended claims.

4.2. Compounds of the Invention

[0073] The present invention encompasses novel compounds and the uses ofthese novel compounds to effectively treat chronic obstructive pulmonarydisorder such as emphysema, cancer and dermatological disorders. Theinvention encompasses treating chronic obstructive pulmonary disordersand related disorders, cancer and dermatological disorders whilereducing or avoiding adverse effects associated with natural andsynthetic retinoids when used at therapeutic levels. Adverse effectsassociated with retinoids at therapeutic levels include, but are notlimited to, the toxic effects of hypervitaminosis A, such as headache,fever, skin and membrane dryness, bone pain, nausea and vomiting,psychiatric disorders and gastrointestinal disorders.

[0074] In one embodiment, the present invention provides compoundshaving the structural formula (I):

[0075] or a pharmaceutically acceptable salt, solvate or hydrate thereofwherein:

[0076] n is an integer from 0 to 2;

[0077] A is aryl or heteroaryl;

[0078] B is O, S or NR⁶;

[0079] R⁶ is hydrogen or alkyl;

[0080] Y is —OR⁷, —SR⁷ or —NR⁸R⁹;

[0081] R⁷ is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl orcycloalkyl-alkyl;

[0082] R⁸ and R⁹ are independently hydrogen, alkyl, aryl, arylalkyl,cycloalkyl or cycloalkyl-alkyl or together with the nitrogen atom towhich they are attached form a heterocycloamino ring;

[0083] Z is —C(R¹⁰¹)₂O—, —R¹⁰²C═CR¹⁰²—, —C≡C—, —C(R¹⁰³)₂S—, —C(O)O— or—C(O)NR¹⁰—;

[0084] each of R¹⁰, R¹⁰¹, R¹⁰² and R¹⁰³ is independently hydrogen oralkyl;

[0085] R¹ and R² are independently hydrogen or alkyl;

[0086] R³ is hydrogen or alkyl; and

[0087] R⁴ and R⁵ are independently hydrogen, (C₁-C₈) alkyl or arylalkyl.

[0088] In a preferred embodiment, A has the structural formula (II):

[0089] wherein:

[0090] R¹¹ and R¹² are independently hydrogen, acyl, acylamino, alkoxy,alkoxycarbonyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, carbamoyl, carboxy, cyano, dialkylamino, halo, haloalkyl,hydroxy, hydroxyalkyl or nitro. In certain embodiments, R¹¹ and R¹² areindependently hydroxy, alkoxy, alkyl, haloalkyl, halo or hydrogen.Preferably, R¹¹ and R¹² are hydrogen or in other preferred embodimentsR¹¹ and R¹² are different and are either fluorine or hydrogen.

[0091] In still another embodiment, Y is OR⁷ and R⁷ is hydrogen ormethyl, preferably hydrogen.

[0092] In another embodiment, n is 1 and R³ is hydrogen.

[0093] In still another embodiment, R¹ and R² are alkyl. Preferably, R¹and R² are methyl.

[0094] In preferred embodiments, Z is —C(R¹⁰¹)₂O—, —R¹⁰²C═CR¹⁰²—,—C(R¹⁰³)₂S—, —C(O)O— or —C(O)NR¹⁰—, and R¹⁰¹—, R¹⁰² and R¹⁰³ arehydrogen. More preferably Z is —CH₂O— or trans —CH═CH—

[0095] In still another embodiment, B is NR⁶. More preferably R⁶ ishydrogen, methyl or ethyl. In still another preferred embodiment, B isNR⁶ and Z is —CH₂O—, trans —HC═CH—, —C≡C—, —C(O)O— or —C(O)NR¹⁰—.

[0096] In still another embodiment, R⁴ is hydrogen. In a preferredembodiment, R⁴ is hydrogen and R⁵ is (C₁-C₈) alkyl or arylalkyl.Preferably, R⁵ is ethyl, pentyl, octyl or benzyl. More preferably, R⁵ ispentyl.

[0097] In one preferred embodiment, B is O and Z is —CH₂O— or trans—HC═CH—. In another preferred embodiment, B is S and Z is —CH₂O—, trans—HC═CH—, —C(O)O— or —C(O)NR¹⁰—.

[0098] In another preferred embodiment, n is 1, Y is OR⁷, R¹ and R² arealkyl, R³ is hydrogen, R⁴ is hydrogen, R⁵ is alkyl or arylalkyl, R⁷ ishydrogen, R¹¹ is hydrogen or halo and R¹² is hydrogen. In a morespecific embodiment, B is NR⁶, Z is —CH₂O—, trans —HC═CH— or —C≡C—, R⁵is alkyl and R⁶ is hydrogen, methyl or ethyl.

[0099] Preferred compounds of the invention include those depicted inTable 1 below. TABLE 1 Example Structure Mass Spec. M. Pt. 5.1 

 91.5-93.3° C. 5.2 

123.0-123.5° C. 5.3 

(M⁻ − 1): 391 5.4 

(M⁻ − 1): 407 5.5 

(M⁺ + 1): 405 5.6 

(M⁺ + 1): 421 5.7 

(M⁺ + 1): 364 5.8 

5.9 

5.10

(M⁺ + 1): 392 5.11

(M⁺ + 1): 423 5.12

(M⁺ + 1): 410 5.13

(M⁺ + 1): 424

5.14

5.15

M⁻: 408 5.16

M⁻: 388

4.3. Synthesis of the Compounds of the Invention

[0100] The compounds of the invention may be obtained via the syntheticmethodology illustrated in Schemes 1-6. Starting materials useful forpreparing compounds of the invention and intermediates thereof arecommercially available or can be prepared by well-known syntheticmethods. Methods other than those illustrated in Schemes 1-6 ofsynthesizing compounds of the invention will be immediately be apparentto those of skill in the art. Accordingly, the synthetic routespresented in Schemes 1-6 are illustrative, rather than comprehensive.Also incorporated by reference is the entire disclosure of copendingU.S. Patent Application U.S. Ser. No. 09/840,486 filed Apr. 23, 2001.

[0101] Those of skill in the art will recognize that a key intermediatein the synthesis of compounds of Formula (I) is the alcohol of Formula(III) shown below where n, B, R¹, R², R³, R⁴ and R⁵ are as defined forFormula (I).

[0102] Scheme 1 illustrates a method for synthesizing alcohols ofFormula (III) when B is either oxygen or sulfur. Commercially availablephenol or thiophenol 33 is converted to alkene 35 or an alkeneequivalent (i.e., a tertiary alcohol) by alkylation or Michael addition.Intramolecular Friedel Crafts cyclization (e.g., AlCl₃) provides theindan 37. Formation of an organometallic indan derivative (e.g., n-butyllithium) followed by quenching with a Weinreb amide gives the ketonewhich may be converted via Wittig chemistry (e.g.,methyltriphenylphosphonium halide and base) to alkene 39. Standardhydroboration-oxidation (e.g., diborane, hydrogen peroxide) providesalcohol 41 (B═O or S).

[0103] Scheme 2 illustrates preparation of alcohols of Formula (III)when B is nitrogen, i.e., quinoline alcohol derivatives 51. Commerciallyavailable 3-nitro phenyl acetic acid is esterified (e.g., Fischeresterification) and alkylated (e.g., cesium carbonate, alkyl halide) toprovide nitro ester 45. The nitro group is reduced (e.g., metal catalystand hydrogen) and acylated to provide alkenyl amide 47, which upontreatment with a Friedel-Crafts catalyst (e.g., AlCl₃) undergoesintramolecular cyclization to provide alcohol 51 after reduction of boththe ester and amide group (e.g., lithium aluminum hydride). It should benoted that alcohol 51 may be converted to a N-alkyl derivative NR⁶ byalkylation or reductive alkylation or in the alternative may beprotected (i.e., carbamate, thioamide, etc.) if this is necessary forsubsequent conversion to compounds of Formula (I).

[0104] It should be noted in Schemes 3-6 that n, A, B, Y, R¹, R², R¹, R⁴and R⁵ are as defined for Formula (I) or are protected precursorsthereto. Typically, compounds where Y is SR⁷ or NR⁸R⁹ are prepared fromthe precursor acid (Y═OH) by activation of the acid and displacementwith the appropriate sulfur or nitrogen nucleophile.

[0105] Scheme 3 illustrates conversion of alcohol 53 to a compound ofFormula (I), where the linking group Z is an alkene. Preferably, whenB═NR⁶ and R⁶ is hydrogen the nitrogen atom is protected beforecommencing the above sequence of steps and deprotected after formationof the olefin (See e.g., Green et al., “Protective Groups in OrganicChemistry”, (Wiley, 2^(nd) ed. 1991)). Alcohol 53 is oxidized toaldehyde 55 (e.g., pyridinium chlorochromate or Swem oxidation) which isreacted with the phosphonate derivative 57 (e.g., prepared byconventional methods such as displacement of the halide with atrialkylphosphonate) in the presence of base to directly providederivative 59.

[0106] Scheme 4 illustrates conversion of alcohol 53 (B═NR⁶, S or O) toa compound of Formula (I), where the linking group Z is an ester(—C(O)O—) or an amide (—C(O)NR¹⁰). As before, when R is hydrogen thenitrogen atom is protected before commencing the above sequence of stepsand deprotected after formation of the ester or amide. Alcohol 53 isoxidized to carboxylic acid 61 (e.g., pyridinium dichromate) which isthen activated (e.g., dicyclohexyldicarbodiimide, dimethylaminopyridine)and reacted with 63 (M is OH or NHR¹⁰) to provide amide or ester 65 X isO or NR¹⁰).

[0107] Scheme 5 illustrates conversion of alcohol 53 (B═NR⁶, S or O) toa compound of Formula (I), where the linking group Z is an alkyne(—C≡C—). As before, when B═NR⁶ and R⁶ is hydrogen the nitrogen atom isprotected before commencing the above sequence of steps and deprotectedafter formation of the alkyne. Alcohol 53 is oxidized to aldehyde 55,which is reacted with the dibromophosphonium ylide 67 to providedibromoalkene 69. Dibromoalkene is converted to an alkyne which is thencoupled to aryl or heteroaryl halide 71 to yield the desired alkyne 73.

[0108] Scheme 6 illustrates conversion of alcohol 53 (B═NR⁶, S or O) toa compound of Formula (I), where the linking group Z is an ether(—CH₂O—) or a thioether (—CH₂S—). As before, when B═NR and R is hydrogenthe nitrogen atom is protected before commencing the above sequence ofsteps and deprotected after formation of the ether or thioether. Alcohol53 is reacted with hydroxy derivative 75 under Mitsonobu conditions(e.g., triphenyl phosphine and diethyl azodicarboxylate) to directlyprovide ether 77. Alternatively, alcohol 53 may be converted to thiol 79(e.g., thiourea, base, then hydrolysis) followed by reaction withhydroxy derivative 75 under Mitsunobu conditions to provide thioether79.

4.4. Assays

[0109] The retinoic acid receptor agonist selectivity of a compound ofthe invention may be determined by using ligand binding assays known tothe skilled artisan (Apfel et al., Proc. Natl. Acad. Sci., 1992, 89,7129; Teng et al., J. Med. Chem., 1997, 40, 2445; Bryce et al., U.S.Pat. No. 5,807,900 which are herein incorporated by reference).Treatment with RAR agonists, particularly RAR γ agonists may promoterepair of alveolar matrix and septation, which are in important intreating emphysema. It should be noted that RAR agonists that are not γselective may be effective in treating emphysema.

[0110] Transactivation, which is the ability of a retinoid to activategene transcription when gene transcription is initiated by the bindingof a ligand to the particular retinoic acid receptor being tested, maybe determined by using methods described in the art (Apfel et al., Proc.Natl. Acad. Sci., 1992, 89, 7129; Bernard et al., Biochem. And Biophys.Res. Comm., 1992, 186, 977 which is herein incorporated by reference).

[0111] The suitability of the compounds of the invention in treatingdermatological disorders caused by light or age and the promotion ofwound healing may be determined by methods described in the art (Mustoeet al., Science 237, 1333 1987; Sprugel et al., J. Pathol., 129, 601,1987, which are herein incorporated by reference). Methods described inthe art may be used to determine the usefulness of the compounds of theinvention to treating dermatological disorders such as acne or psoriasis(Boyd, Am. J. Med., 86, 568, 1989 and references therein; Doran et al.,Methods in Enzymology, 190, 34, 1990, which are herein incorporated byreference). Finally, the ability of the compounds of the invention totreat cancer may also be determined by methods described in the art(Sporn et al., Fed. Proc. 1976, 1332; Hong et al., “Retinoids and HumanCancer” in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn,A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994,597-630, which are herein incorporated by reference).

4.5 Pharmaceutical Compositions and Modes of Administration

[0112] Compounds of the invention disclosed herein are useful forpromoting the repair of damaged alveoli and septation of alveoli. Thus,methods of the invention may be employed to treat pulmonary diseasessuch as emphysema. The methods of treatment using a compound of theinvention disclosed herein also may be used to treat cancer anddermatological disorders.

[0113] When used to treat or prevent emphysema or related diseases,cancer or dermatological disorders, compounds of the invention may beadministered or applied singly or in combination with other agents. Thecompounds of the invention may also be administered or applied singly orin combination with other pharmaceutically active agents including othercompounds of the invention. A compound of the invention can beadministered or applied per se or as pharmaceutical compositions. Thespecific pharmaceutical formulation will depend upon the desired mode ofadministration, and will be apparent to those having skill in the art.Numerous compositions for the oral, topical or parental administrationof retinoid agonists are known in the art. Any of these compositions maybe used to formulate a compound of the invention.

[0114] Pharmaceutical compositions comprising a compound of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the inventioninto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. For topicaladministration a compound of the invention may be formulated assolutions, gels, ointments, creams, suspensions, etc. as are well-knownin the art.

[0115] Systemic formulations include those designed for administrationby injection or infusion e.g., subcutaneous, intravenous, intramuscular,intrathecal or intraperitoneal injection, as well as those designed fortransdermal, transmucosal, oral or pulmonary administration. Systemicformulations may be made in combination with a further active agent thatimproves mucociliary clearance of airway mucus or reduces mucousviscosity. These active agents include but are not limited to sodiumchannel blockers, antibiotics, N-acetyl cysteine, homocysteine andphospholipids.

[0116] For injection, a compound of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks' solution, Ringer's solution, or physiological saline buffer.The solution may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Such compositions are preferablysterile.

[0117] Alternatively, compounds of the invention may be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

[0118] For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art.

[0119] For oral administration, a compound of the invention can bereadily formulated by combination with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. For oral solid formulations suchas, for example, powders, capsules and tablets, suitable excipientsinclude fillers such as sugars, such as lactose, sucrose, mannitol andsorbitol; cellulose preparations such as maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP); granulating agents and binding agents. Ifdesired, disintegrating agents may be added, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate. If desired, solid dosage forms may be sugar-coated orenteric-coated using standard techniques. Methods for formulatingretinoid analogues for oral administration have been described in theart (See, e.g., the formulation of Accutane®, Physicians' Desk Reference54^(th) Ed., p. 2610, 2000). For oral liquid preparations such as, forexample, suspensions, elixirs and solutions, suitable carriers,excipients or diluents include water, saline, alkyleneglycols (e.g.,propylene glycol), polyalkylene glycols (e.g., polyethylene glycol)oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g.,acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM)etc. Additionally, flavoring agents, preservatives, coloring agents,bile salts, acylcarnitines and the like may be added.

[0120] For buccal administration, the compositions may take the form oftablets, lozenges, etc. formulated in conventional manner.

[0121] A compounds of the invention may also be administered directly tothe lung by inhalation for the treatment of cancer, emphysema ordermatological disorders (see e.g., Tong et al., PCT Application, WO97/39745; Clark et al., PCT Application, WO 99/47196, which are hereinincorporated by reference). For administration by inhalation, a compoundof the invention may be conveniently delivered to the lung by a numberof different devices. For example, a Metered Dose Inhaler (“MDI”) whichutilizes canisters that contain a suitable low boiling propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas may beused to deliver compounds of the invention directly to the lung. MDIdevices are available from a number of suppliers such as 3M Corporation,Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome,Schering Plough and Vectura.

[0122] Alternatively, a Dry Powder Inhaler (DPI) device may be used toadminister a compound of the invention to the lung (See, e.g.,. Raleighet al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40,397, which is herein incorporated by reference). DPI devices typicallyuse a mechanism such as a burst of gas to create a cloud of dry powderinside a container, which may then be inhaled by the patient. DPIdevices are also well known in the art and may be purchased from anumber of vendors which include, for example, Fisons, Glaxo-Wellcome,Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. Apopular variation is the multiple dose DPI (“MDDPI”) system, whichallows for the delivery of more than one therapeutic dose. MDDPI devicesare available from companies such as AstraZeneca, GlaxoWellcome, IVAX,Schering Plough, SkyePharma and Vectura. For example, capsules andcartridges of gelatin for use in an inhaler or insufflator may beformulated containing a powder mix of a compound of the invention and asuitable powder base such as lactose or starch for these systems.

[0123] Another type of device that may be used to deliver a compound ofthe invention to the lung is a liquid spray device supplied, forexample, by Aradigm Corporation. Liquid spray systems use extremelysmall nozzle holes to aerosolize liquid drug formulations that may thenbe directly inhaled into the lung.

[0124] In one preferred embodiment, a nebulizer device is used todeliver a compound of the invention to the lung. Nebulizers createaerosols from liquid drug formulations by using, for example, ultrasonicenergy to form fine particles that may be readily inhaled (see e.g.,Verschoyle et al., British J. Cancer, 1999, 80, Suppl. 2, 96, which isherein incorporated by reference). Examples of nebulizers includedevices supplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See,Armer et al., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat.No. 5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974, which areherein incorporated by reference), Aventis and Batelle PulmonaryTherapeutics.

[0125] In another preferred embodiment, an electrohydrodynamic (“EHD”)aerosol device is used to deliver a compound of the invention to thelung. EHD aerosol devices use electrical energy to aerosolize liquiddrug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, PCT Application, WO94/12285; Coffee, PCT Application, WO 94/14543; Coffee, PCT Application,WO 95/26234, Coffee, PCT Application, WO 95/26235, Coffee, PCTApplication, WO 95/32807, which are herein incorporated by reference).The electrochemical properties of a compound of the inventionformulation may be important parameters to optimize when delivering thiscompound to the lung with an EHD aerosol device and such optimization isroutinely performed by one of skill in the art. EHD aerosol devices maymore efficiently deliver drugs to the lung than existing pulmonarydelivery technologies. Other methods of intra-pulmonary delivery of acompound of the invention will be known to the skilled artisan and arewithin the scope of the invention.

[0126] Liquid drug formulations suitable for use with nebulizers andliquid spray devices and EHD aerosol devices will typically include acompound of the invention with a pharmaceutically acceptable carrier.Preferably, the pharmaceutically acceptable carrier is a liquid such asalcohol, water, polyethylene glycol or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of compounds of the invention. Preferably, thismaterial is liquid such as an alcohol, glycol, polyglycol or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat.No. 5,556,611, which are herein incorporated by reference).

[0127] A compound of the invention may also be formulated in rectal orvaginal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0128] In addition to the formulations described previously, a compoundof the invention may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

[0129] Alternatively, other pharmaceutical delivery systems may beemployed. Liposomes and emulsions are well known examples of deliveryvehicles that may be used to deliver a compound of the invention.Certain organic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. A compound of theinvention may also be delivered in a controlled release system. In oneembodiment, a pump may be used (Sefton, CRC Crit. Ref Biomed. Eng.,1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al.,N. Engl. J. Med., 1989, 321, 574). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol.Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard etal., 1989, J. Neurosurg. 71, 105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target of acompound of the invention, e.g., the lung, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115 (1984)).Other controlled-release system may be used (see e.g., Langer, Science,1990, 249, 1527).

[0130] When a compound of the invention is acidic, it may be included inany of the above-described formulations as the free acid, apharmaceutically acceptable salt, a pro-drug, solvate or hydrate.Pharmaceutically acceptable salts substantially retain the activity ofthe free acid and may be prepared by reaction with bases.Pharmaceutically acceptable salts include any known suitable salts ofretinoic acids known in the art for administration to mammals.Pharmaceutical salts tend to be more soluble in aqueous and other proticsolvents than the corresponding free acid form. Similarly, a compound ofthe invention may be included in any of the above-described formulationsas a solvate, hydrate or pro-drug. Preferred pro-drugs includehydrolyzable ester derivatives such as aromatic esters, benzyl estersand lower alkyl esters such as ethyl, cyclopentyl, etc. Other pro-drugsare known to those of skill in the pharmaceutical arts.

4.5 Methods of use, Dosage and Doses

[0131] A compound of the invention, or compositions thereof, willgenerally be used in an amount effective to achieve the intendedpurpose. Of course, it is to be understood that the amount used willdepend on the method of administration.

[0132] For use to treat or prevent chronic obstructive pulmonary diseasesuch as emphysema, cancer or dermatological disorders, compounds of theinvention or compositions thereof, are administered or applied in atherapeutically effective amount. Therapeutically effective amounts ofcompounds of the invention for systemic administration may be found inthe detailed disclosure provided herein.

[0133] The pharmacokinetic profile of the compounds of the invention ispredictable and can be described by using linear pharmacokinetic theory.Importantly, the pharmacokinetics of compounds of the invention inhumans may be readily determined by one of skill in the art. The skilledartisan may determine a range of standard pharmacokinetic parametersafter single oral dosing with a compound of the invention usingprocedures described in the art (see e.g., Khoo et al., J. Clin. Pharm,1982, 22, 395; Colburn et al., J. Clin. Pharm, 1983, 23, 534; Colbum etal., Eur. J. Clin. Pharm., 1983, 23, 689). The skilled artisan may alsomeasure values of these pharmacokinetic parameters after multipledosing, following procedures described in the art, to determine whetherinduction or accumulation of the compound of the invention occurs underthese circumstances (Brazzel et al., Eur. J. Clin. Pharm., 1983, 24,695; Lucek et al., Clin. Pharmacokinetics, 1985, 10, 38). Those of skillin the art may estimate the appropriate systemic dosage levels ofcompounds of the invention necessary to treat emphysema, cancer ordermatological disorders in mammals (preferably, humans) using thepharmacokinetic parameters determined by the above procedures inconjunction with animal model dosage data.

[0134] Dosage amounts and intervals may be adjusted individually toprovide plasma levels of a compound of the invention which aresufficient to maintain therapeutic effect. Usual patient dosages foradministration by injection range from 0.1 μg and about 10.0 mg,preferably, between about 1.0 μg and about 1.0 mg, more preferably,between about 10.0 μg and about 300.0 μg, most preferably between about50.0 μg and about 200 μg. Therapeutically effective serum levels may beachieved by administering a single daily dose or multiple doses eachday.

[0135] The amount of a compound of the invention administered will, ofcourse, be dependent on, among other factors, the subject being treated,the subject's weight, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician. Forexample, the dosage may be delivered in a pharmaceutical composition bya single administration, by multiple applications or controlled release.Dosing may be repeated intermittently, may be provided alone or incombination with other drugs and will continue as long as required foreffective treatment of emphysema.

[0136] Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating emphysema, cancer or dermatological disorders when comparedto other retinoid agonists. The dosage of a compound of the inventionsdescribed herein will preferably be within a range of circulatingconcentrations that include the effective dose with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition (see, e.g.,Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p. 1). For example, a therapeutically effective dose of a compound ofthe invention may be administered either orally or directly into thelung.

5. EXAMPLES

[0137] The invention is further defined by reference to the followingexamples describing in detail the preparation of the compound andcompositions of the invention. It will be apparent to those skilled inthe art that many modifications, both to materials and methods, may bepracticed without departing from the scope of the invention.

Example 5.1 Synthesis of(RAC)-4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic Acid

[0138]

[0139] Step 1

[0140] A solution of 3-bromophenol (10.0 g, 57.8 mmole) in 50 mL ofethyl acrylate was treated with 0.9 mL of Triton B. The reaction mixturewas heated at reflux for 18 hours. Excess ethyl acrylate was removed bydistillation at atmospheric pressure. The resulting residue was dilutedwith 50 mL toluene and co-evaporated. The remaining product was dilutedin 100 mL ether and washed with two 50 mL portions of sodium carbonatesolution, 50 mL water and 50 mL saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a pale yellow liquid. The product waspurified by flash chromatography (SiO₂, 5% ethyl acetate in hexanes) toafford 6.435 g of 3-(3-bromo-phenoxy)-propionic acid ethyl ester as acolorless liquid.

[0141] Step 2

[0142] A solution of 3-(3-bromo-phenoxy)-propionic acid ethyl ester(6.435 g, 23.6 mmole) in 50 mL of anhydrous THF at 0° C. was treateddropwise with 23.6 mL of 3M methylmagnesium chloride solution in THF.The reaction mixture was kept at 0° C. for 30 minutes, allowed to warmto room temperature over 15 hours, carefully quenched by the addition of100 mL saturated aqueous ammonium chloride solution and then extractedwith three 50 mL portions of ether. The combined organic extracts weredried over MgSO₄, filtered and concentrated in vacuo to give a paleyellow oil. The product was purified by flash chromatography (SiO₂, 20%ethyl acetate in hexanes) to yield 5.741 g of4-(3-bromo-phenoxy)-2-methyl-butan-2-ol as a translucent oil.

[0143] Step 3

[0144] A solution of 4-(3-bromo-phenoxy)-2-methyl-butan-2-ol (5.741 g,22.2 mmole) in 45 mL of nitromethane was added dropwise to a suspensionof aluminum chloride (4.019 g, 30.1 mmole) in 45 mL of nitromethane. Thereaction mixture was stirred at room temperature for two hours and thenpoured onto 300 mL of ice-water. The pH was adjusted to 2.0 with 10% HCland the product was extracted with three 100 mL portions of ether. Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a purple oil. The product was purified byflash chromatography (SiO₂, 1% ethyl acetate in hexanes) to yield 4.667g of 7-bromo-4,4-dimethyl-chroman as a colorless oil, which containedabout 16% of 5-bromo-4,4-dimethyl-chroman.

[0145] Step 4

[0146] A solution of 7-bromo-4,4-dimethyl-chroman (1.0 g, 4.15 mmole) in20 mL of THF at −78° C., was treated with 1.91 mL of 2.5M butyllithium.After 30 minutes at −78° C. a solution of hexanoic acidmethoxy-methyl-amide (0.726 g, 4.56 mmole) in 5 mL of THF was added. Thereaction mixture was stirred at −78° C. for 30 minutes, warmed to roomtemperature, quenched by the addition of 25 mL saturated aqueousammonium chloride solution and extracted with three 25 mL portions ofether. The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 5% ethyl acetate in hexanes) to yield 0.516g of 1-(4,4-dimethyl-chroman-7-yl)-hexan-1-one as a colorless oil.

[0147] Step 5

[0148] A suspension of methyl triphenylphosphonium bromide (1.062 g,2.97 mmole) in 20 mL of THF at 0° C. was treated dropwise with 1.2 mL ofa 2.5M butyllithium solution. The mixture was stirred at roomtemperature for 30 minutes and then cooled to 0° C. A solution of1-(4,4-dimethyl-chroman-7-yl)-hexan-1-one (0.516 g, 1.98 mmole) in 5 mLof THF was added to the ylide solution. The reaction mixture was stirredat room temperature for one hour, quenched by the addition of 25 mLwater and extracted with three 25 mL portions of ether. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo to give a yellow solid. The product was purified by flashchromatography (SiO₂, 2% ethyl acetate in hexanes) to yield 0.442 g of4,4-dimethyl-7-(1-methylene-hexyl)-chroman as a colorless oil.

[0149] Step 6

[0150] A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-chroman (0.442g, 1.71 mmole) in 8 mL of THF at 0° C. was treated with 1.71 mL of 1MBH₃.THF complex. The reaction mixture was stirred at room temperaturefor three hours and then cooled to 0° C. The mixture was treatedsuccessively with 0.3 mL of water, 0.34 mL of 3M sodium hydroxide and0.34 mL of 30% hydrogen peroxide, stirred at room temperature for twohours and then diluted with 10 mL of water. The pH was adjusted to 4.0with 10% HCl and extracted with three 12.5 ML portions of ether. Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a pale yellow oil. The product waspurified by flash chromatography (SiO₂, 10-20% ethyl acetate in hexanes)to yield 0.366 g of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol as acolorless oil.

[0151] Step 7

[0152] A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.366 g,1.32 mmole) in 27 mL of THF was treated with 0.222 g of methyl4-hydroxybenzoate, 0.382 g of triphenylphosphine and 0.23 mL of diethylazodicarboxylate (DEAD). The reaction mixture was heated at reflux fortwo hours, diluted with 50 mL of ether and then washed with two 25 mLportions of water and 25 mL of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 7% ethyl acetate in hexanes) to yield 0.474g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methylester, as a pale yellow oil.

[0153] Step 8

[0154] A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoicacid methyl ester (0.474 g, 1.15 mmole) in 8 mL of ethanol was treatedwith a solution of potassium hydroxide (1.3 g) in 5 mL of water. THF (4mL) was added and the mixture was heated at 45° C. for two hours,diluted with 20 mL of water and the pH was adjusted to 2 withconcentrated HCl. The mixture was then extracted with three 20 mLportions of ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to give a pale yellow foam.The product was purified by recrystallization from acetonitrile/water toyield 0.362 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoicacid (1) as a white solid. M.p.: 91.5-93.3° C.

Example 5.2 Synthesis of(RAC)-4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic Acid

[0155]

[0156] Step 1

[0157] A solution of 3-bromothiophenol (5.0 g) in 60 mL of DMF wastreated with 3.75 g of ground potassium carbonate and 3.2 mL of3,3-dimethylallyl bromide. The reaction mixture was stirred at roomtemperature for two hours, poured onto 75 mL of ice-water, acidified topH 2.0 with 10% HCl and extracted with three 75 mL portions of ether.The organic phase was dried over MgSO₄, filtered and concentrated invacuo to give a yellow oil. The product was purified by short pathdistillation (T=170° C. at 950 mTorr) to give 5.651 g of1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene as a colorless liquid.

[0158] Step 2

[0159] A solution of 1-bromo-3-(3-methyl-but-2-enylsulfanyl)-benzene(5.651 g, 22 mmole) in 100 mL of toluene was treated with 5.433 g ofp-toluenesulfonic acid monohydrate and heated at reflux for 15 hours.The mixture was diluted with 100 mL of water, neutralized with solidsodium bicarbonate and extracted with two 100 mL portions of ethylacetate. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byshort path distillation (T=190° C. at 1.08 Torr) to give 4.902 g of7-bromo-4,4-dimethyl-thiochroman as a pale yellow oil, which containedapproximately 20% 5-bromo-4,4-dimethyl-thiochroman.

[0160] Step 3

[0161] A solution of 7-bromo-4,4-dimethyl-thiochroman (2.0 g, 7.78mmole) in 45 mL of THF at −78° C. was treated with 3.9 mL of 2.5Mbutyllithium. After 30 minutes at −78° C. a solution of hexanoic acidmethoxy-methyl-amide (1.486 g, 9.33 mmole) in 5 mL of THF was added. Thereaction mixture was stirred at −78° C. for 30 minutes, warmed to roomtemperature, quenched by the addition of 50 mL of saturated aqueousammonium chloride solution and extracted with three 50 mL portions ofether. The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 3% ethyl acetate in hexanes) to yield 1.183g of 1-(4,4-

[0162] dimethyl-thiochroman-7-yl)-hexan-1-one as a pale yellow oil.

[0163] Step 4

[0164] A suspension of methyl triphenylphosphonium bromide (2.293 g,6.42 mmole) in 40 mL of THF at 0° C., was treated dropwise with 2.6 mLof 2.5M butyllithium. The mixture was stirred at room temperature for 30minutes and then cooled to 0° C. A solution of1-(4,4-dimethyl-thiochroman-7-yl)-hexan-1-one (1.183 g, 4.28 mmole) in10 mL of THF was added to the ylide solution. The reaction mixture wasstirred at room temperature for one hour, quenched by the addition of 50mL water and was extracted with three 50 mL portions of ether. Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow solid. The product was purifiedby flash chromatography (SiO₂, 1% ethyl acetate in hexanes) to yield0.939 g of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman as a colorlessoil.

[0165] Step 5

[0166] A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-thiochroman(0.939 g, 3.42 mmole) in 15 mL of THF at 0° C., was treated with 3.42 mLof 1M BH₃.THF complex. The reaction mixture was stirred at roomtemperature for three hours and then cooled to 0° C. The mixture wastreated successively with 0.59 mL of water, 0.67 mL of 3M sodiumhydroxide and 0.67 mL of 30% hydrogen peroxide. The reaction mixture wasstirred at room temperature for two hours and then diluted with 20 mL ofwater. The pH was adjusted to 4.0 with 10% HCl and then extracted withthree 25 mL portions of ether. The combined organic extracts were driedover MgSO₄, filtered and concentrated in vacuo to give a pale yellowoil. The product was purified by flash chromatography (SiO₂, 10% ethylacetate in hexanes) to yield 0.532 g of2-(4,4-dimethyl-thiochroman-7-yl)-heptan-1-ol as a colorless oil.

[0167] Step 6

[0168] A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.532 g,1.82 mmole) in 35 mL of THF was treated with 0.304 g of methyl4-hydroxybenzoate, 0.525 g of triphenylphosphine and 0.32 mL of diethylazodicarboxylate (DEAD). The reaction mixture was heated at reflux fortwo hours, diluted with 70 mL of ether and washed with two 35 mLportions of water and 35 mL of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 5% ethyl acetate in hexanes) to yield 0.715g of 4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid methylester as a pale yellow oil.

[0169] Step 7

[0170] A solution of4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid methylester (0.715 g, 1.68 mmole) in 12 mL of ethanol was treated with asolution of potassium hydroxide (1.9 g) in 7.5 mL of water. THF (5 mL)was added and the mixture was heated at 45° C. for two hours, dilutedwith 30 mL of water and the pH adjusted to 2.0 with concentrated HCl.The mixture was extracted with three portions of 30 mL of ethyl acetate.The organic phase was dried over MgSO₄, filtered and concentrated invacuo to give a pale yellow foam. The product was purified bytrituration in pentane, to yield 0.617 g of4-[2-(4,4-dimethyl-thiochroman-7-yl)-heptyloxy]-benzoic acid as anoff-white solid. M.p.: 123.0-123.5° C.

Example 5.3 Synthesis of (RAC)4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic Acid

[0171]

[0172] Step 1

[0173] To a solution of oxalyl chloride (0.15 mL) in 9 mL ofdichloromethane at −78° C. was added 0.19 mL of DMSO. The mixture wasstirred at −78° C. for 5 minutes and then a solution of2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.22 g, 0.79 mmole, fromExample 1) in 3 mL of dichloromethane was added. The mixture was stirredat −78° C. for 15 minutes then 0.56 mL of triethylamine was added.Stirring was continued at −78° C. for another 15 minutes then at roomtemperature for two hours. The reaction mixture was quenched by theaddition of 20 mL of water, extracted with three 20 mL portions ofdichloromethane and the combined organic extracts were washed with two20 mL portions of water and 20 mL of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 10% ethyl acetate in hexanes) to afford 0.16g of 2-(4,4-dimethyl-chroman-7-yl)-heptanal as a colorless oil.

[0174] Step 2

[0175] A solution of 4-(diethoxyphosphorylmethyl)-benzoic acid methylester (0.25 g, 0.87 mmole) in 5 mL of THF at −20° C., was treated with0.88 mL of 1M lithium bis(trimethylsilyl)amide solution in hexanes. Themixture was stirred at −20° C. for 20 minutes before a solution of2-(4,4-dimethyl-chroman-7-yl)-heptanal (0.16 g, 0.58 mmole) in 5 mL ofTHF was added. The reaction mixture was stirred at −20° C. for 30minutes, at room temperature for 6 hours, quenched by the addition of 10mL of saturated aqueous ammonium chloride solution and extracted withthree 10 mL portions of ethyl acetate. The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo, to give ayellow oil. The product was purified by flash chromatography (SiO₂, 10%ethyl acetate in hexanes) to yield 0.1 g of4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid methyl esteras a colorless oil.

[0176] Step 3

[0177] A solution of4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid methyl ester(0.1 g, 0.25 mmole) in 25 mL of a 4:1 THF/methanol mixture was treatedwith a solution of 0.1 g of lithium hydroxide monohydrate in 5 mL ofwater. The reaction mixture was stirred at 40° C. for 2 hours,concentrated in vacuo and the pH adjusted to 3-4 with 1N HCl solution.The mixture was extracted with three 25 mL portions of ethyl acetate.The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give 0.06 g of4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid as a colorlessglassy oil. MS (EI): (M⁻−1): 391.

Example 5.4 Synthesis of (RAC)4-[3-(4,4-Dimethyl-Thiochroman-7yl)-oct-1-enyl]-benzoic Acid

[0178]

[0179] Following the procedure described in Example 3, but substituting2-(4,4-dimethyl-thiochroman-7-yl)-heptan-1-ol (from example 2) for2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol in step 1, afforded4-[3-(4,4-dimethyl-thiochroman-7-yl)-oct-1-enyl]-benzoic acid as acolorless glassy oil. MS (EI): (M⁻1): 407.

Example 5.5 Synthesis of(RAC)-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-oct-1-enyl]-benzoicAcid

[0180]

[0181] Step 1

[0182] A solution of 3-nitrophenyl acetic acid (12.755 g, 70.4 mmole) in150 mL of ethanol was treated with 3.83 mL of concentrated sulfuricacid. The reaction mixture was heated at reflux for 20 hours,concentrated in vacuo to ⅓ the initial volume and diluted with 250 mL ofethyl acetate. The organic solution was successively washed with two 100mL portions of water, two 100 mL portions of saturated aqueous sodiumbicarbonate solution, 100 mL of water and 100 mL of saturated aqueoussodium chloride solution. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo to give 14.69 g of ethyl3-nitrophenyl acetate as a pale yellow oil.

[0183] Step 2

[0184] A solution of ethyl 3-nitrophenyl acetate (4.0 g, 19.1 mmole) in80 mL of DMF was treated with 12.46 g of cesium carbonate and 2.55 mL ofpentyl iodide. The reaction mixture was stirred at room temperature for15 hours, diluted with 200 mL of water and extracted with three portionsof 150 mL of ether. The combined organic extracts were washed with 200mL water and 200 mL of saturated aqueous sodium chloride solution. Theorganic phase was dried over MgSO₄, filtered and concentrated in vacuoto give a yellow oil. The product was purified by flash chromatography(SiO₂, 5% ethyl acetate in hexanes) to yield 4.451 g of2-(3-nitro-phenyl)-heptanoic acid ethyl ester as a pale yellow oil.

[0185] Step 3

[0186] A solution of 2-(3-nitro-phenyl)-heptanoic acid ethyl ester(4.451 g, 15.9 mmole) in 150 mL of ethyl acetate containing 1.69 g of10% palladium on carbon was subjected to atmospheric pressure ofhydrogen for 15 hours. The mixture was filtered through a Celite/SiO₂pad and the volatiles were removed in vacuo to yield 3.866 g of2-(3-amino-phenyl)-heptanoic acid ethyl ester as a pale yellow oil.

[0187] Step 4

[0188] A solution of 2-(3-amino-phenyl)-heptanoic acid ethyl ester(3.866 g, 15.5 mmole) in 40 mL of chloroform was treated with 1.73 mL of3,3-dimethylacryloyl chloride. The mixture was heated at reflux for fourhours, quenched by the addition of 100 mL water and extracted with three50 mL portions of chloroform. The combined organic extracts were washedwith 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL ofwater and 100 mL of saturated aqueous sodium chloride solution. Theorganic phase was dried over MgSO₄, filtered and concentrated in vacuoto give a yellow oil. The product was purified by flash chromatography(SiO₂, 15% ethyl acetate in hexanes) to yield 3.822 g of2-[3-(3-methyl-but-2-enoylamino)-phenyl]-heptanoic acid ethyl ester as apale yellow oil.

[0189] Step 5

[0190] A solution of 2-[3-(3-methyl-but-2-enoylamino)-phenyl]-heptanoicacid ethyl ester (3.822 g, 11.5 mmole) in 60 mL of dichloromethane wastreated with 4.613 g of aluminum chloride and heated at reflux for fourhours. The reaction mixture was poured onto 200 mL of ice-water andextracted with two 100 mL portions of dichloromethane. The combinedorganic extracts were washed with 200 mL of saturated aqueous sodiumbicarbonate solution. The organic phase was dried over MgSO₄, filteredand concentrated in vacuo to give a yellow oil. The product was purifiedby flash chromatography (SiO₂, 25% ethyl acetate in hexanes) to yield3.657 g of2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-heptanoic acidethyl ester as a pale yellow oil.

[0191] Step 6

[0192] A solution of2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-heptanoic acidethyl ester (3.657 g, 11 mmole) in 100 mL of ether was treated with 1.6g of lithium aluminum hydride, heated at reflux for four hours and thencooled to 0° C. The reaction mixture was quenched by the successiveaddition of 1.6 mL water, 1.6 mL 15% sodium hydroxide solution and 4.8mL water and stirred at room temperature until a white precipitateformed. MgSO₄ was added and the mixture was filtered and concentrated invacuo affording a yellow oil. The product was purified by flashchromatography (SiO₂, 25% ethyl acetate in hexanes) to yield 2.1 g of2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol as a paleyellow oil.

[0193] Step 7

[0194] A solution of2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (2.1 g,7.62 mmole) in 30 mL of THF was treated with 32 mL of a 1M sodiumbis(trimethylsilyl)amide solution in THF. The reaction mixture wasstirred at room temperature for 30 minutes and then a solution of 3.5 gof di-t-butyl dicarbonate in 30 mL of THF was added. The mixture wasstirred at room temperature for 15 hours, quenched by the addition of100 mL saturated aqueous ammonium chloride solution and extracted withthree 100 mL portions of ether. The combined organic phases were driedover MgSO₄, filtered and concentrated in vacuo to give an orange oil.The residue was taken up in 100 mL of methanol and treated with 10 mL of1% potassium carbonate aqueous solution. The mixture was stirred at roomtemperature for two hours, concentrated in vacuo and the residue dilutedwith 200 mL of ether. The organic solution was washed with two 100 mLportions of water and 100 mL of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a dark yellow oil. The product waspurified by flash chromatography (SiO₂, 10% ethyl acetate in hexanes) toyield 0.757 g of7-(1-hydroxymethyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a yellow oil.

[0195] Step 8

[0196] A solution of7-(1-hydroxymethyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (1.27 g, 3.38 mmole) in 10 mL of dichloromethanewas added to a suspension of 1.1 g of pyridinium chlorochromate in 15 mLof dichloromethane. The reaction mixture was stirred at room temperaturefor 6 hours, diluted with 50 mL of ether and filtered through a pad ofCelite. The volatiles were removed in vacuo to give a brown oil. Theproduct was purified by flash chromatography (SiO₂, 5% ethyl acetate inhexanes) to yield 0.91 g of7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a yellow oil.

[0197] Step 9

[0198] A solution of 4-(dimethoxyphosphorylmethyl)-benzoic acid methylester (0.94 g, 3.6 mmole) in 10 mL of THF at −20° C., was treated with3.7 mL of 1M lithium bis(trimethylsilyl)amide solution in hexanes. After20 minutes at −20° C. a solution of7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.91 g, 2.4 mmole) in 5 mL of THF was added. Thereaction mixture was stirred at −20° C. for 30 minutes, at roomtemperature for 6 hours, quenched by the addition of 10 mL of saturatedaqueous ammonium chloride solution and extracted with three 10 mLportions of ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to give a yellow oil. Theproduct was purified by flash chromatography (SiO₂, 5% ethyl acetate inhexanes) to yield 0.98 g of7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a pale yellow oil.

[0199] Step 10

[0200] A solution of7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.98 g) in 10 mL of dichloromethane was treatedwith 1.5 mL of trifluoroacetic acid. The mixture was stirred at roomtemperature for four hours and then was concentrated in vacuo to yield0.72 g of4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid methyl ester as a yellow oil.

[0201] Step 11

[0202] A solution of4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid methyl ester (0.36 g, 0.88 mmole) in 10 mL of THF was cooled to−78° C. and was treated with 1.1 mL of a 1M lithiumbis(trimethylsilyl)amide solution in hexanes. After 30 minutes at −78°C., 0.06 mL of methyl iodide was added. The mixture was stirred at roomtemperature for 7 hours, quenched by the addition of 10 mL of saturatedaqueous ammonium chloride solution and extracted with two 10 mL portionsof ethyl acetate. The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to give a yellow oil. The product waspurified by flash chromatography (SiO₂, 5% ethyl acetate in hexanes) toyield 0.23 g of4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid methyl ester as a pale yellow oil.

[0203] Step 12

[0204] A solution of4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid methyl ester (0.23 g, 0.5 mmole) in 10 mL of a 1:1 THF/methanolmixture was treated with a solution of 0.09 g of lithium hydroxidemonohydrate in 2.5 mL of water and stirred at 40° C. for 6 hours. Themixture was diluted with 10 mL of water and the pH adjusted to 2.0 with2N HCl solution. The mixture was extracted with three 10 mL portions ofethyl acetate. The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to give a yellow oil. The product waspurified by preparative tlc (SiO₂, 25% ethyl acetate in hexanes) toyield 0.095 g of4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid as a pale yellow oil. MS (EI): (M⁺): 405.

Example 5.6 Synthesis of(RAC)-4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-oct-1-enyl]-benzoicAcid

[0205]

[0206] Following the procedure described in Example 5.5, butsubstituting ethyl iodide for methyl iodide in step 11, afforded4-[3-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid as a pale yellow oil. MS (EI): (M⁺+1): 421.

Example 5.7 Synthesis of(RAC)-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-pent-1-enyl]-benzoicAcid

[0207]

[0208] Following the procedure described in Example 5.5, butsubstituting ethyl iodide for pentyl iodide in step 2, afforded4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-pent-1-enyl]-benzoicacid as a pale yellow oil.

Example 5.8 Synthesis of(RAC)-4-[3-(1,4,4-TRIMETHYL-1,2,3,4-tetrahydro-ouinolin-7-yl)-undec-1-enyl]-benzoicAcid

[0209]

[0210] Following the procedure described in Example 5, but substitutingoctyl iodide for pentyl iodide in step 2, affords4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-undec-1-enyl]-benzoicacid as a pale yellow oil.

Example 5.9 Synthesis of(RAC)-4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-but-1-enyl]-benzoic

[0211]

[0212] Following the procedure described in Example 5.5, butsubstituting benzyl bromide for pentyl iodide in step 2, affords4-[4-phenyl-3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-but-1-enyl]-benzoicacid as a pale yellow oil.

Example 5.10 Synthesis of(RAC)-4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-oct-1-enyl]-benzoicAcid

[0213]

[0214] Following the procedure described in Example 5.5, but eliminatingstep 11 (no N-alkylation) afforded4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid as a pale yellow oil. MS (EI) (M⁺+1): 392.

Example 5.11 Synthesis of(RAC)-3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic

[0215]

[0216] Following the procedure described in Example 5.5, butsubstituting 3-fluoro-4-(dimethoxyphosphorylmethyl)-benzoic acid methylester in step 9 for 4-(dimethoxyphosphorylmethyl)-benzoic acid methylester afforded3-fluoro-4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoicacid as a pale yellow oil. MS (EI) (M⁺+1): 423.

Example 5.12 Synthesis of(RAC)-4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)-heptyloxy]-benzoicAcid

[0217]

[0218] Step 1

[0219] A solution of2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (fromExample 5.5, step 6) (2.52 g, 9.15 mmole) in 35 mL of acetonitrile wascooled to 0° C. and treated with 6.68 mL of a 37% formaldehyde solution,5.82 g of sodium triacetoxyborohydride and 2.36 mL of acetic acid. Thereaction mixture was stirred at 0° C. for 30 minutes then at roomtemperature for four hours, diluted with 50 mL of water and extractedwith two 50 mL portions of ethyl acetate. The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo to give ayellow oil. The product was purified by flash chromatography (SiO₂, 25%ethyl acetate in hexanes) to yield 2.39 g of2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol as apale yellow oil.

[0220] Step 2

[0221] A solution of2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (1.2 g,4.15 mmole) in 20 mL of THF was treated with 0.69 g of methyl4-hydroxybenzoate, 1.2 g of triphenylphosphine and 0.72 mL of diethylazodicarboxylate (DEAD) and heated at reflux for 6 hours. The mixturewas diluted with 100 mL of ethyl acetate and washed with two 50 mLportions of water and 50 mL of saturated aqueous sodium chloridesolution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 10% ethyl acetate in hexanes) to yield 1.1 gof4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoicacid methyl ester, as a pale yellow oil.

[0222] Step 3

[0223] A solution of4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoicacid methyl ester (1.1 g, 2.6 mmole) in 14 mL of a 1:1 THF/methanolmixture was treated with a solution of 0.44 g of lithium hydroxidemonohydrate in 5 mL of water and stirred at 40° C. for 6 hours. Themixture was diluted with 20 mL of water and the pH was adjusted to 2.0with 2N HCl solution. The mixture was extracted with three 20 mLportions of ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to give a yellow oil. Theproduct was purified by preparative tlc (SiO₂, 25% ethyl acetate inhexanes) to yield 0.875 g of4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoicacid as a pale yellow oil. MS (EI): (M⁺+1): 410.

Example 5.13 Synthesis of(RAC)-4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-ouinolin-7-yl)heptyloxy]-benzoicAcid

[0224]

[0225] Following the procedure described in Example 5.12, butsubstituting acetaldehyde for formaldehyde in step 1, afforded4-[2-(1-ethyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoicacid as a pale yellow oil. MS (EI): (M⁺+1): 424.

Example 5.14 Synthesis of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic Acid

[0226]

[0227] Step 1

[0228] A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.2 g,0.72 mmol, from Example 5.1, Step 6) in 1.5 mL of CCL₄ and 2.2 mL ofwater containing 4 mg RuCl₃ was treated with 628 mg, 2.94 mmol of NaIO₄.The mixture was stirred at room temperature for 2.5 h, diluted with 10mL of water and the pH adjusted to 2 with 10% aqueous HCl. The mixturewas extracted with dichloromethane, concentrated to dryness, andpurified via flash chromatography (0-20% ethyl acetate/hexane gradientelution) to give 105 mg (50%) of 2-(4,4-dimethyl-chroman-7-yl)-heptanoicacid.

[0229] Step 2

[0230] A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid (105mg, 0.36 mmol) in 5 mL of dichloromethane with 91.6 mg, 0.4 mmol ofbenzyl 4-hydroxybenzoate and 44 mg, 0.36 mmol of DMAP was cooled to 0°C. and treated with 83 mg, 0.4 mmol of DCC. The mixture was kept at 0°C. for 15 minutes, then warmed to room temperature. After 2 h, themixture was filtered and the resulting solution was washed with waterand brine. The solution was dried and concentrated, then purified byflash chromatography (8% ethyl acetate/hexane) to give 152 mg (84%) of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid benzylester.

[0231] Step 3

[0232] A solution of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid benzyl ester(152 mg, 0.3 mmol) in 10 mL of elthyl acetate with 32 mg of 10%palladium on carbon, was subjected to 1 atm. H₂. After 2 h, the mixturewas filtered through Celite and silica gel, concentrated under vacumnand purified by flash chromatography (gradient elution, 10-50% ethylacetate/hexane) to afford 74 mg (59%) of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoyloxy]-benzoic acid.

Example 5.15 Synthesis of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic Acid

[0233]

[0234] Step 1

[0235] To a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.27g, 0.98 mmole, from Example 1, step 6) in a mixture of 2 mL of carbontetrachloride, 2 mL acetonitrile and 3 mL water, containing 3-5 mg ofruthenium chloride, was added 0.85 g of sodium periodate. The mixturewas stirred at room temperature for 2 hours, diluted with 10 mL ofwater, and pH was adjusted to 2 with 10% hydrochloric acid. The mixturewas extracted with three 10 mL portions of dichloromethane. The organicphase was dried over MgSO₄, filtered and concentrated in vacuo to give adark oil. The product was purified by flash chromatography (SiO₂,gradient from 0 to 20% ethyl acetate in hexanes) to yield 0.16 g of2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid as a pale yellow oil.

[0236] Step 2

[0237] A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid (0.16g, 0.55 mmole) in 8 mL of dichloromethane was treated with 1 mL ofoxalyl chloride and 0.06 mL of DMF. The reaction mixture was stirred atroom temperature for 2 hours and concentrated in vacuo. The residue wasdissolved in 5 mL of pyridine, and 0.17 g of methyl 4-aminobenzoate wasadded. The reaction mixture was stirred at 40° C. for 18 hours, dilutedwith 10 mL of water and extracted with three 10 mL portions of ethylacetate. Combined extracts were washed with 10 mL of 1N hydrochloricacid, 10 mL of water and 10 mL of brine. The organic phase was driedover MgSO₄, filtered and concentrated in vacuo to give an oil. Theproduct was purified by flash chromatography (SiO₂, 20% ethyl acetate inhexanes) to yield 0.15 g of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic acid methylester as a white foam.

[0238] Step 3

[0239] A solution of4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic acid methylester (0.15 g, 0.35 mmole) in 10 mL of a 4:1 THF/methanol mixture wastreated with a solution of 0.1 g of lithium hydroxide monohydrate in 2.5mL of water and stirred at 40° C. for 6 hours. The mixture was dilutedwith 10 mL of water and the pH adjusted to 2.0 with 2N HCl solution. Themixture was extracted with three 10 mL portions of ethyl acetate. Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to give a yellow oil. The product was purified byflash chromatography (SiO₂, 10% methanol in dichloromethane) to yield0.11 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic acidas a white powder. MS (ESI): (M⁻): 408.

Example 5.16 Synthesis of4-[3-(4,4-dimethyl-1,3,3,4-tetrahydro-qunolin-7-yl)-oct-1-ynyl]-benzoicAcid

[0240]

[0241] Step 1

[0242] To a solution of carbon tetrabromide (0.32 g, 0.96 mmole) in 5 mLof dichloromethane, at −20° C., was added triphenyl phosphine in 5 mL ofdichloromethane. After stirring at 0° C. for 15 minutes reaction mixturewas treated with a solution of7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.18 g, 0.48 mmole, from Example 5 step 8) in 2mL of dichloromethane. The reaction mixture was stirred at roomtemperature for 4 hours, quenched by the successive addition of 5 mL ofwater and 1.5 mL of saturated sodium bicarbonate. The phases wereseparated and aqueous phase was extracted with two 25 mL portions ofdichloromethane. Organic phase was dried over MgSO₄, filtered andconcentrated in vacuo affording a brownish thick oil. The product waspurified by flash chromatography (SiO₂, 20% ethyl acetate in hexanes) toyield 0.08 g of7-(3,3-dibromo-1-pentyl-allyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a colourless oil.

[0243] Step 2

[0244] A solution of7-(3,3-dibromo-1-pentyl-allyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.08 g, 0.15 mmole) in 2 mL of THF at −78° C. wastreated with 0.13 mL of 2.5M butyllithium. The reaction mixture wasstirred at −78° C. for 1 hour, then at room temperature for 2 hours,quenched by the successive addition of 5 mL water and 5 mL of saturatedaqueous ammonium chloride solution and extracted with three 25 mLportions of ether. The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to give a yellow oil. The product waspurified by flash chromatography (SiO₂, 5% ethyl acetate in hexanes) toyield 0.049 g of4,4-dimethyl-7-(1-pentyl-prop-2-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a colourless oil.

[0245] Step 3

[0246] A mixture of 0.043 g of methyl 4-iodobenzoate, 0.093 mL oftriethylamine, 4.6 mg of Pd(Ph₃P)₂Cl₂ and 2.5 mg of copper (I) iodide in2 ml of DMF was degassed and treated with a solution of4,4-dimethyl-7-(1-pentyl-prop-2-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.049 g, 0.13 mmole) in 1 mL of DMF. The reactionmixture was stirred at room temperature for 18 hours, diluted with 10 mLof water and extracted with three 10 mL portions of ethyl acetate. Thecombined organic extracts were washed with 10 mL of 1N HCl, 10 mL ofwater and 10 ml of brine, dried over MgSO₄, filtered and concentrated invacuo to give a yellow oil. The product was purified by flashchromatography (SiO₂, 10% ethyl acetate in hexanes) to yield 0.035 g of7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

[0247] Step 4

[0248] A solution of7-[3-(4-methoxycarbonyl-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.035 g, 0.07 mmole) in 5 mL of a 4:1THF/methanol mixture was treated with a solution of 0.1 g of lithiumhydroxide monohydrate in 2 mL of water and stirred at 40° C. for 2hours. The mixture was diluted with 5 mL of water and the pH adjusted to2 with 2N HCl solution. The mixture was extracted with three 10 mLportions of ethyl acetate. The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to give 0.03 g of7-[3-(4-carboxy-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as a yellow oil

[0249] Step 5

[0250] A solution of7-[3-(4-carboxy-phenyl)-1-pentyl-prop-2-ynyl]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (0.035 g, 0.07 mmole) in 2 mL of a 1:1TFA/dichloromethane mixture was stirred for 30 minutes and concentrated.The residue was dissolved in 5 mL of dichloromethane and washed with 5ml of saturated sodium bicarbonate, 5 mL of water and 5 mL of brine, theorganic layer was dried over MgSO₄, filtered and concentrated in vacuoto give 0.02 g of4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-ynyl]-benzoicacid as brownish oil. MS (ESI): (M⁻): 388.

6. Biological Assays Example 6.1 Binding Affinity to and Transactivationof Retinoid Receptors

[0251] The retinoic acid receptor agonist selectivity of a compound ofthe invention may be determined by using ligand binding assays known tothe skilled artisan (Apfel et al., Proc. Natl. Acad. Sci., 1992, 89,7129; Teng et al., J. Med. Chem., 1997, 40, 2445; Bryce et al., U.S.Pat. No. 5,807,900 which are herein incorporated by reference).Treatment with RAR agonists, particularly RAR γ agonists may promoterepair of alveolar matrix and septation, which are in important intreating emphysema. It should be noted that RAR agonists that are not γselective may be effective in treating emphysema.

[0252] Transactivation, which is the ability of a retinoid to activategene transcription when gene transcription is initiated by the bindingof a ligand to the particular retinoic acid receptor being tested, maybe determined by using methods described in the art (Apfel et al., Proc.Natl. Acad. Sci., 1992, 89, 7129; Bernard et al., Biochem. And Biophys.Res. Comm., 1992, 186, 977 which is herein incorporated by reference).

[0253] Binding affinities of selected compounds of the invention areshown below. Binding IC50 nM Example Structure α/β/γ 5.1

3921/3162/3768 5.2

2065/3005/3226 5.3

6920/2919/3868 5.4

1579/1487/2326 5.5

1455/1938/1417 5.6

1284/1474/1000 5.7

3386/1053/>10000  5.10

5139/8272/6390  5.11

6287/3263/4064  5.12

3174/4146/5436  5.13

2516/3125/3603

Example 6.2 Dermatological and Antitumour Assays

[0254] The suitability of the compounds of the invention in treatingdermatological disorders caused by light or age and the promotion ofwound healing may be determined by methods described in the art (Mustoeet al., Science 237, 1333 1987; Sprugel et al., J. Pathol., 129, 601,1987, which are herein incorporated by reference). Methods described inthe art may be used to determine the usefulness of the compounds of theinvention to treating dermatological disorders such as acne or psoriasis(Boyd, Am. J. Med., 86, 568, 1989 and references therein; Doran et al.,Methods in Enzymology, 190, 34, 1990, which are herein incorporated byreference). Finally, the ability of the compounds of the invention totreat cancer may also be determined by methods described in the art(Spom et al., Fed. Proc. 1976, 1332; Hong et al., “Retinoids and HumanCancer” in The Retinoids: Biology, Chemistry and Medicine, M. B. Sporn,A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994,597-630, which are herein incorporated by reference).

Example 6.3 Measurement of Alveolar Repair in Rat Lung with Compounds ofthe Invention

[0255] Compounds of the invention may be evaluated for their effects onalveolar repair in the rat model of elastase-induced emphysema (Massaroet al., Nature, 1997, Vol. 3, No. 6: 675; Massaro et al., U.S. Pat. No.5,998,486). Preferably, animals are divided into treatment groups ofapproximately eight. Lung inflammation and alveolar damage may beinduced in male Sprague Dawley rats by a single instillation of about 2U/gram body mass of pancreatic elastase (porcine derived, Calbiochem).

[0256] Animals may be treated with a compound of the inventionformulated Miglyol at convenient oral dosage ranges (preferably, betweenabout 10.0 mg/kg and 0.0001 mg/kg) and will be dosed orally once per daystarting 21 days post injury. Control groups are challenged withelastase and 21 days later are treated with vehicle (Miglyol) for 14days. Animals were sacrificed 24 hours after the last dose byexsanguination under deep anesthesia. Blood was collected at time ofexsanguination for analysis.

[0257] The lungs are inflated with 10% neutral buffered formalin byintratracheal instillation at a constant rate (1 ml/gram body mass/min).The lung is excised and immersed in fixative for 24 hours prior toprocessing. Standard methods were used to prepare 5 μm paraffinsections. Sections were stained with Hematoxylin and Eosin. Alveolarmeasurements were made in four regions of the lung/rat by ComputerizedMorphometric analysis. The mean value/treatment group may be determinedby summing the average area/rat for all eight rats/treatment groups andrepair of elastase damage expressed as percentage of repair relative tothe elastase+vehicle treated group from the following calculation: %Alveolar Repair: Data is given for,4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid, Compound 9. Dose [μg/kg], p.o.% Alveolar repair 100 60.9 10 54 1 65

7. Formulation Examples Example 7.1 Oral Formulation

[0258] Table 2 provides the ingredients for a tablet dosage form of acompound of the invention: TABLE 2 Component Quantity per Tablet (mg)Compound of the invention 0.1-10.0 Lactose 125.0 Corn Starch 50Magnesium Stearate 0.5 Croscarmellose Sodium 25

[0259] The active ingredient (i.e., a compound of the invention) isblended with the lactose until a uniform mixture is formed. Theremaining ingredients are mixed intimately with the lactose mixture andare then pressed into single scored tablets.

Example 7.2 Oral Formulation

[0260] Capsules of a compound of the invention suitable for thetreatment of emphysema may be made using the ingredients provided inTable 3. TABLE 3 Component Quantity per capsule (mg) Compound of theinvention 0.1-5.0 Lactose 148 Magnesium Stearate  2

[0261] The above ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Example 7.3 Suspension Formulation

[0262] TABLE 4 Component Amount Compound of the invention 0.1 g-1.0 gFumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propylparaben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 gVeegum K (Vanderbilt Co.) 1.0 g Flavorings 0.035 ml Colorings 0.5 mgDistilled water q.s. to 100 ml

[0263] The above ingredients listed in Table 4 are mixed to form asuspension for oral administration.

Example 7.4 Injectable Formulation

[0264] TABLE 5 Component Amount Compound of the invention 0.02 g-0.2 gSodium acetate buffer solution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q.s.to suitable pH Distilled water q.s. to 20 ml

[0265] The above ingredients listed in Table 5 are mixed to form aninjectable formulation.

Example 7.5 Injectable Formulation

[0266] TABLE 6 Component Amount (mg/ml) Compound of the invention 2.0-20Citric acid 0.2 Sodium citrate 2.6 Benzalkonium chloride 0.2 Sorbitol 35Sodium taurocholate or glycholate 10

[0267] The above ingredients are mixed to form an injectableformulation.

Example 7.6 Nasal Formulation

[0268] TABLE 7 Component Amount Compound of the invention 0.2 g Sodiumacetate buffer solution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q.s. tosuitable pH Distilled or sterile water q.s to 20 ml

[0269] The above ingredients are mixed to form a suspension for nasaladministration.

Example 7.7 Inhalation Formulation

[0270] TABLE 8 Component Percentage by weight Compound of the invention(stabilized with 1.0 □α-tocopherol) 1,1,2-tricholoro-trifluoroethane26.1 40% by weight dichlorodifluoromethane and 72.0 60% by weight1,2-dichloro-1,1,2,2 tetraflouroethane

[0271] A compound of the invention is dissolved carefully in1,1,2-tricholoro-1,2,2 trifluoroethane without evaporation of anysolvent and the resultant solution is filtered and stored in a sealedcontainer. The resultant solution and the propellant gas may beintroduced into aerosol cans for dispensation in the percentages shownin Table 8 using methods known to the skilled artisan. A metering valvewhich is designed for a discharge of between 100 μg and 300 μg per sprayshot may be employed to deliver the correct dosage of the compound ofthe invention.

Example 7.8 Inhalation Formulation of a Compound of the Invention

[0272] TABLE 9 Component Percentage by weight Compound of the invention(stabilized with 0.5 □α-tocopherol) Emulsifier (i.e., Cremophor RH 40)22.0 1,2 propylene glycol 2.0 Water and carrier gas ad 100% by weight

[0273] Cremaphor RH 40 may be purchased from BASF corporation. Otheremulsifiers or solutizers are known to those of skill in the art and maybe added to the aqueous solvent instead of Cremaphor RH 40. A compoundof the invention, emulsifier, 1,2 propylene glycol and water are mixedtogether to form a solution. The above liquid formulation may be used,for example, in a pressurized gas aerosol with an appropriate carriergas (e.g., nitrogen or carbon dioxide).

Example 7.9 EHD Formulation of a Compound of the Invention

[0274] TABLE 10 Component Percentage by weight Compound of the invention(stabilized with 0.1 □α-tocopherol) Emulsifier (i.e., Cremophor RH 40)10.0 Polyethylene glycol 3.0 Water 86.9

[0275] A compound of the invention, emulsifier, polyethylene glycol andwater are mixed together to form a solution. The above liquidformulation may be used in typical EHD devices known in the art.

[0276] The embodiments of the invention described above are intended tobe merely exemplary, and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A compound according to structural formula (I):

or a pharmaceutically acceptable salt, solvate or hydrate thereofwherein: n is an integer from 0 to 2; A is aryl or heteroaryl; Bis O, Sor NR⁶; R is hydrogen or alkyl; Y is —OR⁷, —SR⁷ or —NR⁸R⁹; R⁷ ishydrogen, alkyl, aryl, arylalkyl, cycloalkyl or cycloalkyl-alkyl; R⁸ andR⁹ are independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl orcycloalkyl-alkyl or together with the nitrogen atom to which they areattached form a heterocycloamino ring; Z is —C(R¹⁰¹)₂O—, —R¹⁰²C═CR¹⁰²—,—C≡C—, —C(R¹⁰³)₂S—, —C(O)O— or —C(O)NR¹⁰—; each of R¹⁰, R¹⁰¹, R¹⁰² andR¹⁰³ is independently hydrogen or alkyl; R¹ and R² are independentlyhydrogen or alkyl; R³ is hydrogen or alkyl; and R⁴ and R⁵ areindependently hydrogen, (C₁-C₈) alkyl or arylalkyl.
 2. The compound ofclaim 1, wherein Y is OR⁷ and R⁷ is hydrogen or alkyl.
 3. The compoundof claim 2, wherein A has the structural formula (II):

wherein: R¹¹ and R¹² are independently hydrogen, acyl, acylamino,alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, carbamoyl, carboxy, cyano, dialkylamino, halo, haloalkyl,hydroxy, hydroxyalkyl or nitro.
 4. The compound of claim 3, wherein R¹¹and R¹² are independently hydroxy, alkoxy, alkyl, haloalkyl, halo orhydrogen.
 5. The compound of claim 4, wherein R¹¹ and R¹² are hydrogen.6. The compound of claim 4, wherein R¹¹ and R¹² are independentlyfluorine or hydrogen.
 7. The compound of claim 2, wherein n is 1 and R³is hydrogen.
 8. The compound of claim 7, wherein R¹ and R² are methyl.9. The compound of claim 8, wherein R⁷ is hydrogen.
 10. he compound ofclaim 2, wherein R¹ and R² are independently alkyl.
 11. The compound ofclaim 10, wherein R¹ and R² are methyl.
 12. The compound of claim 11wherein Z is —C(R¹⁰¹)₂O—, —R¹⁰²C═CR¹⁰²—, —C(R¹⁰²)₂S—, —C(O)O— or—C(O)NR¹⁰—, and R¹⁰¹, R¹⁰² and R¹⁰³ are hydrogen.
 13. The compound ofclaim 12, wherein Z is —CH₂O— or trans —CH═CH—.
 14. The compound ofclaim 13, wherein B is NR⁶.
 15. The compound of claim 1, wherein B isNR⁶.
 16. The compound of claim 15, wherein Y is OR⁷ and R⁷ is hydrogenor alkyl.
 17. The compound of claim 16, wherein n is one and R³ ishydrogen.
 18. The compound of claim 17, wherein A has the structuralformula (II):

wherein: R¹¹ and R¹² are independently hydrogen, acyl, acylamino,alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, carbamoyl, carboxy, cyano, dialkylamino, halo, haloalkyl,hydroxy, hydroxyalkyl or nitro.
 19. The compound of claim 18, whereinR¹¹ and R¹² are independently hydroxy, alkoxy, alkyl, haloalkyl, halo orhydrogen.
 20. The compound of claim 19, wherein R¹¹ and R¹² arehydrogen.
 21. The compound of claim 19, wherein R¹¹ and R¹² areindependently fluorine or hydrogen.
 22. The compound of claim 19,wherein R¹ and R² are methyl.
 23. The compound of claim 1, wherein R⁴ ishydrogen.
 24. The compound of claim 23, wherein wherein Y is OR⁷ and R⁷is hydrogen or alkyl.
 25. The compound of claim 24, wherein n is one andR³ is hydrogen.
 26. The compound of claim 25 wherein R¹ and R² aremethyl.
 27. The compound of claim 26, wherein R⁵ is (C₁-C₈) alkyl orarylalkyl.
 28. The compound of claim 27, wherein R⁵ is ethyl, pentyl,octyl or benzyl.
 29. The compound of claim 28, wherein A has thestructural formula (II):

wherein: R¹¹ and R¹² are independently hydrogen, acyl, acylamino,alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl,alkylthio, carbamoyl, carboxy, cyano, dialkylamino, halo, haloalkyl,hydroxy, hydroxyalkyl or nitro.
 30. The compound of claim 29, whereinR¹¹ and R¹² are independently hydroxy, alkoxy, alkyl, haloalkyl, halo orhydrogen.
 31. The compound of claim 30, wherein R⁷ is hydrogen.
 32. Thecompound of claim 31, wherein R¹¹ and R¹² are hydrogen.
 33. A method oftreating an obstructive airway disorder in a mammal comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1, or a pro-drug thereof. 34.The method of claim 33 wherein the disorder is chronic obstructivepulmonary disease.
 35. The method of claim 34, wherein the disorder isemphysema.
 36. A method of treating cancer in a mammal comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1, or a pro-drug thereof.
 37. Amethod of treating a dermatological disorder in a mammal comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1, or a pro-drug thereof.
 38. Acomposition suitable for treating a mammal suffering from emphysemacomprising an amount of a compound of claim 1 or a pro-drug thereof, anda carrier, said amount being sufficient to alleviate one symptom ofemphysema.
 39. A composition suitable for treating a mammal sufferingfrom cancer comprising an amount of a compound of claim 1 or a pro-drugthereof, and a carrier, said amount being sufficient to alleviate onesymptom of cancer.
 40. A composition suitable for treating a mammalsuffering from a dermatological disease comprising an amount of acompound of claim 1 or a pro-drug thereof, and a carrier, said amountbeing sufficient to alleviate one symptom of the dermatological disease.41. A method for treating emphysema and related disorders comprisingdelivering a formulation of a compound of claim 1, or a pro-drugthereof, into the lungs of a mammal.
 42. A method for treating emphysemacomprising combining the use of a compound of claim 1, or a pro-drugthereof, with one or more additional therapies.
 43. A method fortreating cancer comprising combining the use of a compound of claim 1,or a pro-drug thereof, with one or more additional therapies.
 44. Amethod for treating a dermatological disorder comprising combining theuse of a compound of claim 1, or a pro-drug thereof, with one or moreadditional therapies.